Evaluating the effectiveness of nicotine replacement therapy in critically ill smokers: A meta-analysis of randomized controlled trials

INTRODUCTION The effectiveness of nicotine replacement therapy (NRT) in critically ill patients remains uncertain, as conflicting research results have been reported. Despite potential side effects and inconsistent data on safety and efficacy, NRT is still prescribed in intensive care units (ICUs) to prevent withdrawal symptoms and manage agitation in patients who are smokers. This meta-analysis aimed to assess the effectiveness of nicotine replacement therapy in critically ill smoking patients. METHODS A systematic review and meta-analysis of randomized controlled trials investigated the outcomes of smokers admitted to ICUs and were randomized either to receive or not receive nicotine replacement therapy (NRT) during their ICU stay. The MEDLINE and Embase databases were searched from inception through 13 February 2023 using OVID. The primary outcome was ICU length of stay (LOS) for this systematic review and meta-analysis. Meta-analysis was conducted using both random-effects and fixed-effect models; the latter is recommended when meta-analysis is restricted to just a few studies. The study was registered in the Prospective International Register of Systematic Reviews (PROSPERO) under reference number CRD42023407804. RESULTS Of 28 studies initially identified, three, with 67 patients on NRT and 72 controls, were deemed eligible for pooled analysis. Patients who received NRT experienced a shorter LOS (mean difference, MD= -3.06; 95% CI: -5.88 – -0.25, p=0.0, I2=0%). The mechanical ventilation (MV) duration was also shorter in the NRT group, but this difference was not statistically significant (MD= -1.24; 95% CI: -3.21–0.72, p=0.22, I2=12.69%). Delirium duration was reported by two studies, from which pooled analysis revealed an MD of -0.50 (95% CI: -1.63–0.62, I2=0%). The vasopressor duration was assessed in two studies, and the overall MD for vasopressor duration was not statistically different between NRT patients and controls in the fixed-effects model (MD=0.11; 95% CI: -0.75–0.96, I2=0%). CONCLUSIONS Critically ill smoker patients who received NRT experienced a significantly shorter ICU LOS but no significant differences in the durations of MV, vasopressor use, or delirium.

(Nicotine replacement therapy OR NRT OR nicotine replacement OR Nicotine gums OR nicotine patch OR nicotine nasal spray OR nicotine inhaler OR nicotine lozenge OR Tobacco Cessation Product*).tw.Table 2. Explanation for using each domain of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach 1

A -Risk of Bias
Our confidence in an estimate of effect decreases if studies suffer from major limitations that are likely to result in a biased assessment of the intervention effect.For randomized trials, these methodological limitations include failure to generate a random sequence, lack of allocation sequence concealment, lack of blinding (particularly with subjective outcomes that are highly susceptible to biased assessment), a large loss to follow-up or selective reporting of outcomes.
Every study addressing a particular outcome will differ, to some degree, in the risk of bias.Review authors should make an overall judgement on whether the certainty of evidence for an outcome warrants downgrading on the basis of study limitations.The assessment of study limitations should apply to the studies contributing to the results in the 'Summary of findings' table, rather than to all studies that could potentially be included in the analysis.
A rating of high certainty evidence can be achieved only when most evidence comes from studies that met the criteria for low risk of bias.The certainty of evidence might be downgraded by one level when most of the evidence comes from individual studies either with a crucial limitation for one item, or with some limitations for multiple items.

B -Inconsistency
When studies yield widely differing estimates of effect (heterogeneity or variability in results), investigators should look for robust explanations for that heterogeneity.For instance, drugs may have larger relative effects in sicker populations or when given in larger doses.If an important modifier exists, with good evidence that important outcomes are different in different subgroups (which would ideally be pre-specified), then a separate 'Summary of findings' table may be considered for a separate population.When heterogeneity exists and affects the interpretation of results, but review authors are unable to identify a plausible explanation with the data available, the certainty of the evidence decreases.

C -Indirect evidence
Two types of indirectness are relevant.First, a review comparing the effectiveness of alternative interventions (say A and B) may find that randomized trials are available, but they have compared A with placebo and B with placebo.Thus, the evidence is restricted to indirect comparisons between A and B.
Second, a review may find randomized trials that meet eligibility criteria but address a restricted version of the main review question in terms of population, intervention, comparator or outcomes.Other sources of indirectness may arise from interventions studied (e.g. if in all included studies a technical intervention was implemented by expert, highly trained specialists in specialist centres, then evidence on the effects of the intervention outside these centres may be indirect), comparators used (e.g. if the comparator groups received an intervention that is less effective than standard treatment in most settings) and outcomes assessed (e.g.indirectness due to surrogate outcomes when data on patient-important outcomes are not available, or when investigators seek data on quality of life but only symptoms are reported).Review authors should make judgements transparent when they believe downgrading is justified, based on differences in anticipated effects in the group of primary interest.

D -Imprecision
When studies include few participants or few events, and thus have wide confidence intervals, review authors can lower their rating of the certainty of the evidence.

E-Publications bias
The certainty of evidence level may be downgraded if investigators fail to report studies on the basis of results (typically those that show no effect: publication bias) or outcomes (typically those that may be harmful or for which no effect was observed: selective outcome non-reporting bias).If a large number of studies included in the review do not contribute to an outcome, or if there is evidence of publication bias, the certainty of the evidence may be downgraded.A prototypical situation that may elicit suspicion of publication bias is when published evidence includes a number of small studies, all of which are industryfunded.

References 1 -
Higgins JPT, Green S (editors).Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0[updated March 2011].The Cochrane Collaboration, 2011.Available from www.handbook.cochrane.org.Supplementary Figure 1.Quality assessment results for the three studies included in the meta-analysis,